A new kind of diabetes medication approved by the FDA: is there hope for obesity?
Authors: Danisha Dhirani, Ahmad Shahid, Hassan Mumtaz
Journal: International Journal of Surgery (2023)

Globally, the percentage of people suffering from obesity and type 2 diabetes is constantly increasing. Several epidemiological studies have proven the tight association between diabetes and obesity; it is estimated that more than 80% of type 2 diabetes patients are overweight or obese. Obese individuals with diabetes must be managed with large and persistent weight reduction1. The American Diabetes Association recommends an A1C goal of less than 7%. According to research by the Diabetes Prevention Program, every kilogram lost is associated with a 16% decrease in the development of type 2 diabetes. Moderate weight loss has been associated with decreased insulin resistance, alleviated diabetic complications, reduced cardiovascular disease risk factors, and better glycemic parameters. However, many people with type 2 diabetes find it challenging to reach their blood sugar goals through diet and exercise alone2. On May 13, 2022, the US Food and Drug Administration (FDA) approved a unique, first-in-class medication for the treatment of type 2 diabetes, known as tirzepatide (Mounjaro). It is administered as a once-weekly injection under the skin and has a dual impact, decreasing blood sugar and promoting weight reduction more effectively than the existing treatments for this illness3. Tirzepatide is a dual incretin agonist. Following a meal, the gut releases hormones called incretins, notably glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Incretins stimulate the pancreas to release the glucose-lowering hormone insulin and block the hormone glucagon, which would cause the liver to release stored glucose, hence raising blood glucose levels. Additionally, incretins postpone stomach emptying, which delays the release of glucose into the bloodstream and encourages satiety. Type 2 diabetes patients do not respond, as intensely, to incretin hormones as normal people would. Tirzepatide compensates for this deficiency by activating the GLP-1 and GIP receptors in the body. Both hormones are rapidly released after consumption and appear to be controlled by the nervous system. They stimulate insulin synthesis in pancreatic cells in a glucose-dependent way. Furthermore, GLP-1 inhibits pancreatic glucagon release and has extrapancreatic effects such as direct suppressive action on appetite centers and a delay in stomach emptying, boosting the sense of fullness4. Tirzepatide engages with the GIP receptor more than the GLP-1 receptor, indicating an unbalanced mode of action. Pharmacological investigations suggest that tirzepatide resembles the activities of natural GIP at the GIP receptor but favors cAMP production over arrestin recruitment at the GLP-1 receptor, which coincides with a reduced capacity to induce GLP-1 receptor internalization compared to GLP-1. Experiments in primary islets show that arrestin1 reduces the insulin response to GLP-1 but not to GIP or tirzepatide, implying that tirzepatide's biased agonism increases insulin production5. In five clinical studies, three distinct dosages of tirzepatide (5, 10, and 15 mg) were studied as either stand-alone treatments or as add-ons to existing diabetic medications. Tirzepatide's effectiveness was compared with that of a placebo, a GLP-1 receptor agonist (semaglutide), and two long-acting insulin analogs. When used as a stand-alone therapy, patients randomized to receive the recommended dose of tirzepatide (15 mg) had their hemoglobin A1c level lowered by 1.6% more than placebo, and 1.5% more than placebo, when used in combination with long-acting insulin. In trials comparing tirzepatide with other diabetic drugs, individuals who got the highest recommended dose of tirzepatide had a 0.5% lower HbA1c than semaglutide, a 0.9% lower HbA1c than insulin degludec, and a 1.0% lower HbA1c than insulin glargine. Obesity was prevalent among participants, with an average BMI of 32–34 kg/height in m2 reported at enrollment. The average weight reduction with tirzepatide was 15 pounds greater than placebo when neither was taken with insulin and 23 pounds greater than placebo when both were used with insulin among participants, randomized to the highest indicated dosage. With the highest prescribed dose of tirzepatide, the average weight reduction was 12 pounds greater than with semaglutide, 29 pounds greater than with insulin degludec, and 27 pounds greater than with insulin glargine. Patients who received insulin without tirzepatide gained weight during the trial6. Moreover, ascertaining the weight loss, another recent double-blinded randomized controlled trial was published in NEJM where all patients intervened for Tirzepatide showed a greater tendency to lose weight when compared with patients taking placebo7. However, there were complications with the methodology of the trial; participants involved were more committed to losing weight, thus requiring a change in lifestyle; changes in cardiometabolic variables were not inspected due to insufficient time span; and, lastly, there was a lack of diversity; the study involved fewer patients who were suffering from obesity and an obesity-induced disease simultaneously. The above-stated reasons contributed to imprecise results7. The most prevalent adverse effects of tirzepatide reported by trial participants were nausea, diarrhea, vomiting, and constipation. Severe hypoglycemia happened on rare occasions. Researchers are still studying tirzepatide's long-term safety and possible impacts on cardiovascular events, including heart attack, stroke, and death8. In rats, tirzepatide produces thyroid C-cell tumors, but it is uncertain if tirzepatide produces similar cancers in humans, such as medullary thyroid carcinoma. Additionally, tirzepatide should not be used in people who have a personal or familial history of medullary thyroid cancer or who have multiple endocrine neoplasia type 2, and it has not been examined in individuals with a history of pancreatic inflammation (pancreatitis). Similarly, it is also not recommended for type 1 diabetic patients9. The early clinical development of a multifaceted single pharmacological drug, such as tirzepatide, with the capacity to drastically drop glucose levels, increase insulin sensitivity, reduce weight, and improve dyslipidemia is critical. As a result, tirzepatide appears to be both a novel antidiabetic drug and an antiobesity treatment. It is too early to be unduly optimistic since further research is warranted to evaluate the long-term effects of this drug and adequately validate the possible advantages. Ethical approval Not applicable. Source of funding None. Authors' contribution All authors have equally contributed to the manuscript and have approved the final manuscript to be published. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number None. Guarantor Danisha Dhirani. Provenance and peer review Not commissioned, externally peer-reviewed.